Carboxamide derivatives and their use in the treatment of thromboembolic diseases and tumours

ABSTRACT

Compounds of the formula (I), in which the variables have the following meaning, D is phenyl or pyridyl, each of which is unsubstituted or monosubstituted or polysubstituted by Hal, A, OR 2 , N(R 2 ) 2 , NO 2 , CN, COOR 2  or CON(R 2 ) 2 ; R 1  is H, Ar, Het, cycloalkyl or A, which may be substituted by OR 2 , SR 2 , N(R 2 ) 2 , Ar, Het, cycloalkyl, CN, COOR 2  or CON(R 2 ) 2 ; R 2  is H or A; E is phenylene, which may be monosubstituted or polysubstituted by Hal, A, OR 2 , N(R 2 ) 2 , NO 2 , CN, COOR 2  or CON(R 2 ) 2 , or is piperidine-1,4-diyl; W is AR, Het or N(R 2 ) 2  and, if E=piperidine-1,4-diyl, is alternatively R 2  or cycloalkyl, X is NH or O, are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.

[0001] The invention relates to compounds of the formula I

[0002] in which

[0003] D is phenyl or pyridyl, each of which is unsubstituted ormonosubstituted or polysubstituted by Hal, A, OR², N(R²)₂, NO₂, CN,COOR² or CON(R²)₂,

[0004] R¹ is H, Ar, Het, cycloalkyl or A, which may be substituted byOR², SR², N(R²)₂, Ar, Het, cycloalkyl, CN, COOR² or CON(R²)₂,

[0005] R² is H or A,

[0006] E is phenylene, which may be monosubstituted or polysubstitutedby Hal, A, OR², N(R²)₂, NO₂, CN, COOR² or CON(R²)₂, or ispiperidine-1,4-diyl,

[0007] W is Ar, Het or N(R²)₂ and, if E=piperidine-1,4-diyl, isalternatively R² or cycloalkyl,

[0008] X is NH or O,

[0009] A is unbranched or branched alkyl having 1-10 carbon atoms, inwhich one or two CH₂ groups may be replaced by O or S atoms and/or by—CH═CH— groups and/or in addition 1-7 H atoms may be replaced by F,

[0010] Ar is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR²,CON(R²)₂, NR²COA, NR²SO₂A, COR², SO₂NR², SO₃H or S(O)_(m)A,

[0011] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic radical having from 1 to 4 N, O and/or S atoms,which may be unsubstituted or monosubstituted, disubstituted ortrisubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂, NR²COA,NR²SO₂A, COR², SO₂NR², SO₃H, S(O)_(m)A and/or carbonyl oxygen,

[0012] Hal is F, Cl, Br or I,

[0013] n is 0 or 1,

[0014] m is 0, 1 or 2,

[0015] and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.

[0016] The invention also relates to the optically active forms, theracemates, the diastereomers and the hydrates and solvates, for examplealcoholates, of these compounds.

[0017] The invention had the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

[0018] It has been found that the compounds of the formula I and theirsalts have very valuable pharmacological properties and are welltolerated. In particular, they exhibit factor Xa-inhibiting propertiesand can therefore be employed for combating and preventingthromboembolic illnesses, such as thrombosis, myocardial infarction,arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosisafter angioplasty and claudicatio intermittens.

[0019] The compounds of the formula I according to the invention arefurthermore inhibitors of the coagulation factors factor VIIa, factorIXa and thrombin in the blood coagulation cascade.

[0020] Other aromatic amides are described in WO 99/00121 and in WO00/39118. Aromatic amidine derivatives having an antithrombotic actionare disclosed, for example, in EP 0 540 051 B1. cyclic guanidines forthe treatment of thromboembolic illnesses are described, for example, inWO 97/08165. Aromatic heterocyclic compounds having factor Xa-inhibitoryactivity are disclosed, for example, in WO 96/10022. SubstitutedN-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xainhibitors are described in WO 96/40679.

[0021] The antithrombotic and anticoagulant effect of the compoundsaccording to the invention is attributed to the inhibitory actionagainst activated coagulation protease, known by the name factor Xa, orto the inhibition of other activated serine proteases, such as factorVIIa, factor IXa or thrombin.

[0022] Factor Xa is one of the proteases involved in the complex processof blood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic illnesses. However, inhibition of thrombin may inhibitthe fibrin formation involved in thrombus formation. The inhibition ofthrombin can be measured, for example, by the method of G. F. Cousins etal. in Circulation 1996, 94, 1705-1712.

[0023] Inhibition of factor Xa can thus prevent the formation ofthrombin.

[0024] The compounds of the formula I according to the invention andtheir salts engage in the blood coagulation process by inhibiting factorXa and thus inhibit the formation of thrombuses.

[0025] The inhibition of factor Xa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A suitable method is described, for example, by J. Hauptmann et al. inThrombosis and Haemostasis 1990, 63, 220-223.

[0026] The inhibition of factor Xa can be measured, for example, by themethod of T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

[0027] Coagulation factor VIIa initiates the extrinsic part of thecoagulation cascade after binding to tissue factor and contributes tothe activation of factor X to give factor Xa. Inhibition of factor VIIathus prevents the formation of factor Xa and thus subsequent thrombinformation.

[0028] The inhibition of factor VIIa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A conventional method for the measurement of the inhibition of factorVIIa is described, for example, by H. F. Ronning et al. in ThrombosisResearch 1996, 84, 73-81.

[0029] Coagulation factor IXa is generated in the intrinsic coagulationcascade and is likewise involved in the activation of factor X to givefactor Xa. Inhibition of factor IXa can therefore prevent the formationof factor Xa in a different way.

[0030] The inhibition of factor IXa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A suitable method is described, for example, by J. Chang et al. inJournal of Biological Chemistry 1998, 273, 12089-12094.

[0031] The compounds according to the invention may furthermore be usedfor the treatment of tumours, tumour illnesses and/or tumour metastases.A correlation between tissue factor TF/factor VIIa and the developmentof various types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59.

[0032] The publications listed below describe an antitumoural action ofTF-VII and factor Xa inhibitors for various types of tumour.

[0033] K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;

[0034] E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);

[0035] B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);

[0036] M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92

[0037] The compounds of the formula I can be employed as medicamentactive ingredients in human and veterinary medicine, in particular forthe treatment and prevention of thromboembolic illnesses, such asthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, venous thrombosis, pulmonary embolism, arterialthrombosis, myocardial ischaemia, unstable angina and strokes based onthrombosis.

[0038] The compounds according to the invention are also employed forthe treatment or prophylaxis of atherosclerotic diseases, such ascoronary arterial disease, cerebral arterial disease or peripheralarterial disease. The compounds are also employed in combination withother thrombolytic agents in the case of myocardial infarction,furthermore for prophylaxis for reocclusion after thrombolysis,percutaneous transluminal angioplasty (PTCA) and coronary bypassoperations.

[0039] The compounds according to the invention are furthermore used forthe prevention of rethrombosis in microsurgery, furthermore asanticoagulants in connection with artificial organs or in haemodialysis.

[0040] The compounds are furthermore used in the cleaning of cathetersand medical aids in vivo in patients, or as anticoagulants for thepreservation of blood, plasma and other blood products in vitro. Thecompounds according to the invention are furthermore used for illnessesin which blood coagulation makes a crucial contribution to the course ofthe illness or represents a source of secondary pathology, such as, forexample, in cancer, including metastasis, inflammatory disorders,including arthritis, and diabetes.

[0041] In the treatment of the illnesses described, the compoundsaccording to the invention are also employed in combination with otherthrombolytically active compounds, such as, for example, with “tissueplasminogen activator” t-PA, modified t-PA, streptokinase or urokinase.The compounds according to the invention are given either at the sametime as or before or after the other substances mentioned.

[0042] Particular preference is given to simultaneous administrationwith aspirin in order to prevent recurrence of the clot formation.

[0043] The compounds according to the invention are also used incombination with blood platelet glycoprotein receptor (IIb/IIIa)antagonists, which inhibit blood platelet aggregation.

[0044] The invention relates to the compounds of the formula I and theirsalts and to a process for the preparation of the compounds of theformula I according to claim 1 and their salts, characterised in that

[0045] a) a compound of the formula II

[0046] in which

[0047] R¹, E, W, X and n are as defined in claim 1,

[0048] is reacted with a compound of the formula III

D—N═C═O  III

[0049] in which

[0050] D is as defined in claim 1, or

[0051] b) a compound of the formula IV

H₂N—(CH₂)_(n)—E—W  IV,

[0052] in which E, W and n are as defined in claim 1,

[0053] is reacted with a compound of the formula V

[0054] in which

[0055] L is Cl, Br, I or a free or reactively functionally modified OHgroup, and

[0056] R¹, X and D are as defined in claim 1, or

[0057] d) compounds of the formula I are liberated from one of theirfunctional derivatives by treatment with a solvolysing orhydrogenolysing agent, or

[0058] c) a base or acid of the formula I is converted into one of itssalts.

[0059] The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, monohydrates or dihydrates or alcoholates.

[0060] The term pharmaceutically usable derivatives is taken to mean,for example, the salts of the compounds according to the invention andalso so-called prodrug compounds.

[0061] The term prodrug derivatives is taken to mean, for example,compounds of the formula I which have been modified with, for example,alkyl or acyl groups, sugars or oligopeptides and which are rapidlycleaved in the organism to give the effective compounds according to theinvention. These also include biodegradable polymer derivatives of thecompounds according to the invention, as described, for example, in Int.J. Pharm. 115, 61-67 (1995).

[0062] The invention also relates to mixtures of the compounds of theformula I according to the invention, for example mixtures of twodiastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,1:100 or 1:1000. These are particularly preferably mixtures ofstereoisomeric compounds.

[0063] For all radicals which occur more than once, their meanings areindependent of one another.

[0064] Above and below, the radicals or parameters R¹, D, E, W and n areas defined under the formula I, unless expressly stated otherwise.

[0065] A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methyl-propyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

[0066] A is very particularly preferably alkyl having 1-6 carbon atoms,preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl or trifluoromethyl.

[0067] Cycloalkyl is preferably, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

[0068] Hal is preferably F, Cl or Br, but also I.

[0069] Ar is, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-amino-phenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methylamino-carbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)-phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)-phenyl, o-, m- or p-(N-ethylamino)-phenyl,o-, m- or p-(N,N-diethylamino)-phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methyl-sulfonyl)-phenyl,further preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di-fluorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichloroophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4chlorophenyl.

[0070] Ar is preferably, for example, phenyl which is unsubstituted ormonosubstituted, disubstituted or trisubstituted by Hal, A, OR², SO₂A,COOR² or CN phenyl.

[0071] Ar is particularly preferably, for example, phenyl which isunsubstituted or monosubstituted or disubstituted by Hal, A, OA, SO₂A,SO₂NH₂, COOR² or CN, such as, for example, phenyl,2-methylsulfonylphenyl, 2-amino-sulfonylphenyl, 2-, 3- or4-chlorophenyl, 4-methylphenyl, 4-bromophenyl, 3-fluoro-4-methoxyphenyl,4-trifluoromethoxyphenyl, 4-ethoxyphenyl, 2-methoxyphenyl, 3-cyanophenylor 4-ethoxycarbonylphenyl. Ar is very particularly preferablyunsubstituted phenyl, 4-chlorophenyl or 2-methylsulfonylphenyl.

[0072] Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

[0073] The heterocyclic radicals may also be partially or fullyhydrogenated. Het can thus, for example, also be 2,3-dihydro-2-, -3-,-4- or -5-furyl, 2,5-dihydro-2-, -3-, 4- or 5-furyl, tetrahydro-2- or-3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or-4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl,tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or-4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-,2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, 4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7-, or-8-isoquinolyl 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

[0074] Het is preferably a monocyclic or bicyclic, saturated,unsaturated or aromatic heterocyclic radical having from 1 to 2 N, Oand/or S atoms, which may be unsubstituted or monosubstituted bycarbonyl oxygen. Het is preferably, for example, furyl, thienyl,thiazolyl, imidazolyl, 2,1,3-benzothiadiazolyl, oxazolyl, pyridyl,indolyl, piperidinyl, morpholinyl, tetrahydropyranyl, piperazinyl,pyrazinyl, piperidinyl or pyrrolidinyl, optionally substituted bycarbonyl oxygen, such as, for example, 3-oxomorpholin-4-yl,2-oxopiperidin-1-yl or 2-oxopyrrolidin-1-yl.

[0075] Het is very particularly preferably thienyl, imidazolyl, pyridyl,indolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, morpholinyl,tetrahydropyran-4-yl, 3-oxomorpholin-4-yl, 2-oxo-2H-pyrazin-1-yl,2-oxo-pyrrolidin-1-yl or 2-oxopiperidin-1-yl.

[0076] D is in particular, for example, phenyl which is unsubstituted ormonosubstituted or disubstituted by Hal, A, hydroxyl, methoxy, ethoxy,hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, or pyridyl which isunsubstituted or monosubstituted by Hal.

[0077] D is very particularly preferably 4-chlorophenyl or3-chloro-2-pyridyl.

[0078] R¹ is preferably, for example, H, phenyl or alkyl having 1-6carbon atoms, which may be substituted by thiophene, imidazole, indole,SR², cycloalkyl or phenyl.

[0079] R¹ is in particular, for example, H, methyl, ethyl, propyl,butyl, tert-butyl, pentyl, cyclopropylmethyl, thiophen-2-ylmethyl,imidazol-4-ylmethyl, methylsulfanylethyl, phenyl, benzyl,pyridin-3-ylmethyl, indol-3-ylmethyl, aminopropyl or 3-cyanobenzyl,furthermore pyridin-2-yl, 2- or 4-fluorophenyl or 4-hydroxyphenyl,

[0080] R² is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or6 carbon atoms.

[0081] n is preferably 0 or 1.

[0082] m is preferably 2.

[0083] E is preferably, for example, 1,4-phenylene or 1,4-piperidinyl.

[0084] W is preferably, for example, 2-methylsulfonylphenyl,4-pyridinyl, tetrahydropyran-4-yl, 2-oxopiperidin-1-yl,3-oxomorpholin-4-yl, dimethylamino, diethylamino, piperazinyl,morpholin-4-yl, 2-oxopyrrolidin-1-yl, piperidin-1- or -4-yl or phenyl.

[0085] If E is 1,4-piperidinyl, W is preferably alternatively, forexample, isopropyl, cyclopentyl or cyclohexyl,

[0086] The compounds of the formula I may have one or more chiralcentres and therefore occur in various stereoisomeric forms. The formulaI covers all these forms.

[0087] Accordingly, the invention relates in particular to the compoundsof the formula I in which at least one of the said radicals has one ofthe preferred meanings indicated above. Some preferred groups ofcompounds may be expressed by the following sub-formulae Ia to Im, whichconform to the formula I and in which the radicals not designated ingreater detail are as defined under the formula I, but in which

[0088] in Ia

[0089] D is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, OR² or COOR², or pyridyl which is unsubstitutedor monosubstituted by Hal;

[0090] in Ib

[0091] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic radical having from 1 to 2 N, O and/or S atoms,which may be unsubstituted or monosubstituted by carbonyl oxygen;

[0092] in Ic

[0093] Ar is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR², SO₂A, SO₂NH₂, COOR² orCN;

[0094] in Id

[0095] D is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, hydroxyl, methoxy, ethoxy, hydroxycarbonyl,methoxycarbonyl or ethoxycarbonyl, or pyridyl which is unsubstituted ormonosubstituted by Hal;

[0096] in Ie

[0097] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl;

[0098] in If

[0099] E is 1,4-phenylene or 1,4-piperidinyl;

[0100] in Ig

[0101] Ar is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR², SO₂A, SO₂NH₂, COOR² orCN,

[0102] Het is a monocyclic or bicyclic, saturated, unsaturated oraromatic heterocyclic radical having from 1 to 2 N, O and/or S atoms,which may be unsubstituted or monosubstituted by carbonyl oxygen,

[0103] W is Ar, Het or N(R²)₂ and, if E=piperidine-1,4-diyl, isalternatively R²;

[0104] in Ih

[0105] Ar is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, OA, SO₂A, COOR², SO₂NH₂ or CN,

[0106] Het is thienyl, imidazolyl, pyridyl, indolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, pyrazinyl, 2-oxo-2H-pyrazin-1-yl,morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl,2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl,

[0107] W is Ar, Het or N(R²)₂ and, if E=piperidine-1,4-diyl, isalternatively R²;

[0108] in Ii

[0109] D is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, OR² or COOR², or pyridyl which is unsubstitutedor monosubstituted by Hal,

[0110] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl,

[0111] R² is H or A,

[0112] E is 1,4-phenylene or 1,4-piperidinyl,

[0113] W is Ar, Het or N(R₂)₂ and, if E=piperidine-1,4-diyl, isalternatively R²,

[0114] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃,

[0115] Ar is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, OA, SO₂A, COOR², SO₂NH₂ or CN,

[0116] Het is thienyl, imidazolyl, pyridyl, indolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, pyrazinyl, 2-oxo-2H-pyrazin-1-yl,morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl,2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl,

[0117] Hal is F, Cl or Br,

[0118] n is 0 or 1,

[0119] m is 1 or 2;

[0120] in Ij

[0121] D is phenyl which is unsubstituted or monosubstituted by Hal, orpyridyl which is unsubstituted or monosubstituted by Hal,

[0122] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl,

[0123] R² is H or A,

[0124] E is 1,4-phenylene,

[0125] W is 2-methylsulfonylphenyl,

[0126] X is NH or O,

[0127] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃,

[0128] n is 0,

[0129] and their pharmaceutically tolerated salts and solvates;

[0130] in Ik

[0131] D is phenyl which is unsubstituted or monosubstituted by Hal, orpyridyl which is unsubstituted or monosubstituted by Hal,

[0132] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl,

[0133] R² is H or A,

[0134] E is 1,4-piperidinyl,

[0135] W is Het,

[0136] Het is thienyl, imidazolyl, pyridyl, indolyl, piperidinyl,morpholinyl, piperazinyl, 2-oxopiperazinyl, pyrazinyl,2-oxo-2H-pyrazin-1-yl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl, or2-oxopiperidin-1-yl,

[0137] X is NH or O,

[0138] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃,

[0139] n is 0 or 1;

[0140] in Il

[0141] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl,or phenyl or pyridyl, each of which is monosubstituted by Hal or OH;

[0142] in Im

[0143] D is phenyl which is unsubstituted or monosubstituted by Hal, orpyridyl which is unsubstituted or monosubstituted by Hal,

[0144] R¹ is H, phenyl or alkyl having 1-6 carbon atoms, which may besubstituted by thiophene, imidazole, indole, SR², cycloalkyl or phenyl,

[0145] R² is H or A,

[0146] E is 1,4-piperidinyl,

[0147] W is Het, R² or cycloalkyl,

[0148] Het is thienyl, imidazolyl, pyridyl, indolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, pyrazinyl, 2-oxo-2H-pyrazin-1-yl,morpholinyl, tetrahydropyran-4-yl, 3-oxomorpholin-4-yl or2-oxo-piperidin-1-yl,

[0149] X is NH or O,

[0150] A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃,

[0151] n is 0 or 1,

[0152] and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.

[0153] The compounds of the formula I and also the starting materialsfor the preparation are, in addition, prepared by methods known per se,as described in the literature (for example in the standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

[0154] If desired, the starting materials can also be formed in situ sothat they are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

[0155] Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

[0156] The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali or alkalineearth metal hydroxide, carbonate or bicarbonate or another salt of aweak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium. The addition of an organic base,such as triethylamine, dimethylaniline, pyridine or quinoline, may alsobe favourable. Depending on the conditions used, the reaction time isbetween a few minutes and 14 days, and the reaction temperature isbetween about 0° and 150°, normally between 20° and 130°.

[0157] Examples of suitable inert solvents are water, hydrocarbons, suchas hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

[0158] The starting compounds of the formulae II and III are generallyknown. If they are novel, they can, however, be prepared by methodsknown per se.

[0159] Compounds of the formula I can also be obtained by reactingcompounds of the formula IV with compounds of the formula V. In thecompounds of the formula V, L is preferably Cl, Br, I or a reactivelymodified OH group, such as, for example, an activated ester, animidazolide or alkylsulfonyloxy having 1-6 carbon atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).

[0160] The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali or alkalineearth metal hydroxide, carbonate or bicarbonate or another salt of aweak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium. The addition of an organic base,such as triethylamine, dimethylaniline, pyridine or quinoline or anexcess of the amine component of the formula IV, may also be favourable.Depending on the conditions used, the reaction time is between a fewminutes and 14 days, and the reaction temperature is between about 0°and 150°, normally between 20° and 130°.

[0161] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide or dimethylformamide (DMF); nitriles, such asacetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene; esters, such as ethylacetate, or mixtures of the said solvents.

[0162] Compounds of the formula I can also be obtained by liberatingcompounds of the formula I from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

[0163] Preferred starting materials for the solvolysis or hydrogenolysisare those which conform to the formula I, but contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bonded to an N atom, in particular thosewhich carry an R′—N group, in which R′ is an amino-protecting group,instead of an HN group, and/or those which carry an hydroxyl-protectinggroup instead of the H atom of an hydroxyl group, for example thosewhich conform to the formula I, but carry a —COOR″ group, in which R″ isan hydroxyl-protecting group, instead of a —COOH group.

[0164] It is also possible for a plurality of—identical ordifferent—protected amino and/or hydroxyl groups to be present in themolecule of the starting material. If the protecting groups present aredifferent from one another, they can in many cases be cleaved offselectively.

[0165] The term “amino-protecting group” is known in general terms andrelates to groups which are suitable for protecting (blocking) an aminogroup against chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size is furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,furthermore CBZ, Fmoc, benzyl and acetyl.

[0166] The compounds of the formula I are liberated from theirfunctional derivatives—depending on the protecting group used—forexample using strong acids, advantageously using TFA or perchloric acid,but also using other strong inorganic. acids, such as hydrochloric acidor sulfuric acid, strong organic carboxylic acids, such astrichloroacetic acid, or sulfonic acids, such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but is not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic acids, such as acetic acid,ethers, such as tetrahydrofuran or dioxane, amides, such as DMF,halogenated hydrocarbons, such as dichloromethane, furthermore alsoalcohols, such as methanol, ethanol or isopropanol, and water. Mixturesof the above-mentioned solvents are furthermore suitable. TFA ispreferably used in excess without addition of a further solvent, andperchloric acid is preferably used in the form of a mixture of aceticacid and 70% perchloric acid in the ratio 9:1. The reaction temperaturesfor the cleavage are advantageously between about 0 and about 50°,preferably between 15 and 30° (room temperature).

[0167] The BOC, OBut and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5NHCl in dioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

[0168] Protecting groups which can be removed hydrogenolytically (forexample CBZ, benzyl or the liberation of the amidino group from itsoxadiazole derivative) can be cleaved off, for example, by treatmentwith hydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° and pressures between about 1 and200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZgroup succeeds well, for example, on 5 to 10% Pd/C in methanol or usingammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at20-30°.

[0169] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, trifluoromethylbenzene, chloroform ordichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether or ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

[0170] The biphenyl-SO₂NH₂ group is preferably employed in the form ofits tert-butyl derivative. The tert-butyl group is cleaved off, forexample, using TFA with or without addition of an inert solvent,preferably with addition of a small amount of anisole (1-10% by volume).

[0171] It is furthermore possible to convert a compound of the formula Iinto another compound of the formula I by converting one or more R¹, D,E and/or W radical(s) into one or more R¹, D, E and/or W radical(s), forexample by acylating an amino group or reducing nitro groups to aminogroups (for example by hydrogenation on Raney nickel or Pd/carbon in aninert solvent, such as methanol or ethanol).

[0172] Esters can be saponified, for example, using acetic acid or usingNaOH or KOH in water, water/THF or water/dioxane, at temperaturesbetween 0 and 100°.

[0173] Free amino groups can furthermore be acylated in a conventionalmanner using an acid chloride or anhydride or alkylated using anunsubstituted or substituted alkyl halide, advantageously in an inertsolvent, such as dichloromethane or THF and/or in the presence of abase, such as triethylamine or pyridine, at temperatures between −60 and+30°.

[0174] If W is 1,4-piperidinyl, the alkylation of the piperidinenitrogen can be carried out by conventional methods of reductiveamination.

[0175] A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

[0176] On the other hand, compounds of the formula I can be convertedinto the corresponding metal salts, in particular alkali metal oralkaline earth metal salts, or into the corresponding ammonium saltsusing bases (for example sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate). It is also possible to usephysiologically acceptable organic bases, such as, for example,ethanolamine.

[0177] Compounds of the formula I according to the invention may bechiral owing to their molecular structure and may accordingly occur invarious enantiomeric forms. They can therefore exist in racemic or inoptically active form.

[0178] Since the pharmaceutical activity of the racemates orstereoisomers of the compounds according to the invention may differ, itmay be desirable to use the enantiomers. In these cases, the end productor even the intermediates can be separated into enantiomeric compoundsby chemical or physical measures known to the person skilled in the artor even employed as such in the synthesis.

[0179] In the case of racemic amines, diastereomers are formed from themixture by reaction with an optically active resolving, agent. Examplesof suitable resolving agents are optically active acids, such as the Rand S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, mandelic acid, malic acid, lactic acid, suitable N-protected aminoacids (for example N-benzoylproline) or N-benzenesulfonylproline), orthe various optically active camphorsulfonic acids. Also advantage ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Examplesof suitable eluents for this purpose are aqueous or alcoholic solventmixtures, such as, for example, hexane/isopropanol/acetonitrile, forexample in the ratio 82:15:3.

[0180] The invention furthermore relates to the use of compounds of theformula I and/or their physiologically acceptable salts for thepreparation of pharmaceutical preparations, in particular bynon-chemical methods. They can be converted here into a suitable dosageform together with at least one solid, liquid and/or semiliquidexcipient or assistant and, if desired, in combination with one or morefurther active ingredients.

[0181] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and optionally excipients and/or assistants.

[0182] These medicaments can be used in human or veterinary medicine.Suitable excipients are organic or inorganic substances which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, such as lactose orstarch, magnesium stearate, talc or vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders or also as nasal sprays.The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, to prepare injection preparations. Thepreparations indicated may be sterilised and/or comprise assistants,such as lubricants, preservatives, stabilisers and/or wetting agents,emulsifying agents, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

[0183] The compounds of the formula I and their physiologicallyacceptable salts can be used for combating thromboembolic illnesses,such as thrombosis, myocardial infarction, arteriosclerosis,inflammation, apoplexia, angina pectoris, restenosis after angioplasty,claudicatio intermittens, tumours, tumour diseases and/or tumourmetastases.

[0184] In general, the substances according to the invention arepreferably administered in doses between about 1 and 500 mg, inparticular between 5 and 100 mg, per dosage unit. The daily dose ispreferably between about 0.02 and 10 mg/kg of body weight. However, thespecific dose for each patient depends on a wide variety of factors, forexample on the efficacy of the specific compound employed, on the age,body weight, general state of health, sex, on the diet, on the time andmethod of administration, on the excretion rate, medicament combinationand severity of the particular illness to which the therapy applies.Oral administration is preferred.

[0185] The invention furthermore relates to medicaments comprising atleast one compound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and at least one further medicament active ingredient.

[0186] The invention also relates to a set (kit) consisting of separatepacks of

[0187] (a) an effective amount of a compound of the formula I and/or itspharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios, and

[0188] (b) an effective amount of a further medicament activeingredient.

[0189] The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules each containing an effective amount of a compound of theformula I and/or its pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

[0190] The invention furthermore relates to the use of compounds of theformula I and/or their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of thrombosis, myocardialinfarction, arteriosclerosis, inflammation, apoplexia, angina pectoris,restenosis after angioplasty, claudicatio intermittens, tumours, tumourdiseases and/or tumour metastases, in combination with at least onefurther medicament active ingredient.

[0191] Above and below, all temperatures are given in ° C. In thefollowing examples, ‘conventional work-up’ means that water is added ifnecessary, the pH is adjusted, if necessary, to between 2 and 10,depending on the constitution of the end product, the mixture isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallisation. Rf values on silica gel; eluent: ethylacetate/methanol 9:1.

[0192] Mass spectrometry (MS): EI (electron ionisation) M⁺ESI(electrospray ionisation) (M+H)⁺ FAB (fast atom bombardment) (M+H)⁺

EXAMPLE 1

[0193] 1.1 1.08 g of 4-methylmorpholine are added to a solution of 3.0 gof(R)-2-benzyloxycarbonylamino-3-phenylpropionic acid(Z-D-phenylalanine), 2.52 g of 2′-methylsulfonylbiphenyl-4-ylamine, 1.93g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, hydrochloride(DAPECI) and 1.43 g of 1-hydroxybenzotriazole (HOBt) in 25 ml of DMF,and the mixture is stirred at room temperature for a further 40 hours.The reaction mixture is introduced into water, and the precipitate isfiltered off, giving benzyl[(R)-1-(2′-methylsulfonylbiphenyl-4-ylcarbamoyl)-2-phenylethyl]carbamate(“AA”), ESI 529,

[0194] 1.2 A solution of 4.39 g of “AA” in 50 ml of methanol ishydrogenated using palladium on active carbon as catalyst. The catalystis separated off, the solvent is removed, and the residue ischromatographed over a silica gel column (petroleum ether/ethylacetate), giving(R)-2-amino-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide(“AB”), ESI 395,

[0195] 1.3 81 mg of 4-chlorophenyl isocyanate are added to a solution of200 mg of “AB” in 5 ml of dichloromethane, and the mixture is stirred atroom temperature for a further 4 hours. 200 mg oftris(2-aminoethyl)aminepolystyrene (polyamine resin) are subsequentlyadded, the mixture is stirred at room temperature for a further 18hours, and the resin is separated off. Removal of the solvent gives(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamideESI 548,

[0196] IC₅₀ (Xa)=8.6×10⁻⁸ M;

[0197] IC₅₀ (VIIa)=6.5×10⁻⁸ M;

EXAMPLE 2

[0198] 2.1 A solution of 3.0 g of (R)-2-aminopropionic acid (D-alanine)and 5.63 g of sodium hydrogencarbonate in 50 ml of water is heated to80°. 10.3 g of 4-chlorophenyl isocyanate are added, and the mixture isstirred at 80° for a further 1 hour. Conventional work-up gives(R)-2-[3-(4-chlorophenyl)ureido]propionic acid (“BA”), ESI 243.

[0199] 2.2 28 mg of 4-methylmorpholine are added to a solution of 68 mgof “BA”, 62 mg of 2′-methylsulfonylbiphenyl-4-ylamine (“BB”), 54 mg ofDAPECI and 38 mg of HOBt in 1 ml of DMF, and the mixture is stirred atroom temperature for 40 hours. The reaction mixture is introduced intowater, and the precipitate is filtered off, giving(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-propionamide,ESI 472.

[0200] Analogous reaction of “BB” with

[0201] (S)-2-(3-pyridin-2-ylureido)pentanoic acid,

[0202] (R)-2-(3-phenylureido)pentanoic acid,

[0203] 2-(3-phenylureido)-3-(thiophen-2-yl)propionic acid,

[0204] 2-(3-phenylureido)-3-(3H-imidazol-4-yl)propionic acid,

[0205] 2-(3-phenylureido)hexanoic acid,

[0206] 2-(3-phenylureido)-4-(methylsulfanyl)butyric acid,

[0207] 2-(3-phenylureido)-2-phenylacetic acid,

[0208] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid

[0209] (R)-2-[3-(4-methylphenyl)ureido]-3-phenylpropionic acid

[0210] (R)-2-(3-pyridin-4-ylureido)pentanoic acid,

[0211] (S)-2-(3-pyridin-4-ylureido)pentanoic acid,

[0212] (R)-2-(3-pyridin-2-ylureido)pentanoic acid,

[0213] (S)-2-(3-phenylureido)pentanoic acid,

[0214] (R)-2-(3-pyridin-3-ylureido)pentanoic acid,

[0215] (S)-2-(3-phenylureido)-3-(pyridin-3-yl)propionic acid,

[0216] (S)-2-(3-phenylureido)-3-(indol-3-yl)propionic acid,

[0217] 2-(3-phenylureido)propionic acid,

[0218] 2-(3-phenylureido)acetic acid,

[0219] (S)-2-[3-(3-chlorophenyl)ureido]-3-phenylpropionic acid,

[0220] (S)-2-[3-(4-trifluoromethylphenyl)ureido]-3-phenylpropionic acid,

[0221] (S)-2-[3-(2-chlorophenyl)ureido]-3-phenylpropionic acid,

[0222] (S)-2-[3-(4-ethoxyphenyl)ureido]-3-phenylpropionic acid,

[0223] (S)-2-[3-(4-methylphenyl)ureido]-3-phenylpropionic acid,

[0224] (S)-2-[3-(2-methoxyphenyl)ureido]-3-phenylpropionic acid,

[0225] (S)-2-[3-(4-ethoxycarbonylphenyl)ureido]-3-phenylpropionic acid,

[0226] (R)-2-[3-(3-chlorophenyl)ureido]-3-phenylpropionic acid,

[0227] (R)-2-[3-(4-trifluoromethylphenyl)ureido]-3-phenylpropionic acid,

[0228] (R)-2-[3-(2-chlorophenyl)ureido]-3-phenylpropionic acid,

[0229] (R)-2-[3-(4-ethoxyphenyl)ureido]-3-phenylpropionic acid,

[0230] (R)-2-[3-(2-methoxyphenyl)ureido]-3-phenylpropionic acid,

[0231] (R)-2-[3-(4-ethoxycarbonylphenyl)ureido]-3-phenylpropionic acid,

[0232] 2-(3-phenylureido)-5-BOC-aminovaleric acid,

[0233] (S)-2-(3-phenylureido)-3-phenylpropionic acid,

[0234] (R)-2-(3-phenylureido)-3-phenylpropionic acid,

[0235] (R)-2-[3-(4-chlorophenyl)ureido]-3-cyclopropylpropionic acid,

[0236] 2-[3-(4-chlorophenyl)ureido]-4-(methylsulfanyl)butyric acid,

[0237] (R)-2-[3-(4-chlorophenyl)ureido]propionic acid,

[0238] 2-[3-(4-chlorophenyl)ureido]acetic acid,

[0239] (R)-2-[3-(5-chloro-pyridin-2-yl)ureido]-3-phenylpropionic acid,

[0240] (R)-2-[3-(4-bromophenyl)ureido]-3-phenylpropionic acid,

[0241] (R)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-3-phenylpropionicacid,

[0242] 2-[3-(4-chlorophenyl)ureido]hexanoic acid,

[0243] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0244] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid,

[0245] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid;

[0246] (S)-2-[3-(4-methoxyphenyl)ureido]-3-phenylpropionic acid,

[0247] (S)-2-[3-(4-bromophenyl)ureido]-3-phenylpropionic acid,

[0248] (S)-2-[3-(4-fluorophenyl)ureido]-3-phenylpropionic acid,

[0249] (S)-2-[3-(4-fluorophenyl)ureido]-3-phenylpropionic acid,

[0250] (S)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-3-phenylpropionicacid,

[0251] (R)-2-[3-(4-methoxyphenyl)ureido]-3-phenylpropionic acid,

[0252] (R)-2-[3-(4-bromophenyl)ureido]-3-phenylpropionic acid,

[0253] (R)-2-[3-(4-iodophenyl)ureido]-3-phenylpropionic acid,

[0254] (R)-2-[3-(4-fluorophenyl)ureido]-3-phenylpropionic acid,

[0255] (S)-2-[3-(3-trifluorophenyl)ureido]-3-phenylpropionic acid,

[0256] (R)-2-[3-(3-trifluorophenyl)ureido]-3-phenylpropionic acid,

[0257] gives the following compounds:

[0258](S)-2-(3-pyridin-2-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,ESI 467; IC₅₀ (Xa)=3.8×10⁻⁶ M; IC₅₀ (VIIa)=2.7×10⁻⁶ M;

[0259](R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,ESI 466; IC₅₀ (Xa)=2×10⁻⁶ M; Ic₅₀ (VIIa)=9.3×10⁻⁷ M;

[0260]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(thiophen-2-yl)propionamide,ESI 520; IC₅₀ (Xa)=1.2×10⁻⁶ M; IC₅₀ (VIIa)=75×10⁻⁷ M;

[0261]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(3H-imidazol4-yl)propionamide,ESI 504; IC₅₀ (Xa)=2×10⁻⁶ M; IC₅₀ (VIIa)=2×10⁻⁶ M;

[0262](R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)hexanoamide,ESI 480; IC₅₀ (Xa)=3×10⁻⁶ M; IC₅₀ (VIIa)=1.7×10⁻⁷ M;

[0263]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylsulfanylbutyramide,ESI 498; IC₅₀ (Xa)=2.3×10⁻⁶ M; IC₅₀ (VIIa)=1.8×10⁻⁶ M;

[0264]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide,ESI 500; IC₅₀ (Xa)=2.3×10⁻⁴ M; IC₅₀ (VIIa)=2×10⁻⁶ M;

[0265](S)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 548;

[0266](R)-2-[3-(4-methylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 528;

[0267](R)-2-(3-pyridin-4-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-pentanoamide,ESI 467;

[0268](S)-2-(3-pyridin-4-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-pentanoamide,ESI 467;

[0269](R)-2-(3-pyridin-2-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-pentanoamide,ESI 467;

[0270](S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,ESI 466;

[0271](R)-2-(3-pyridin-3-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-pentanoamide,ESI 467;

[0272](S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(pyridin-3-yl)propionamide,ESI 515;

[0273](S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(indol-3-yl)propionamide,ESI 553;

[0274]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)propionamide, ESI438;

[0275] 2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,ESI 424;

[0276](S)-2-[3-(3-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 548;

[0277](S)-2-[3-(4-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 582;

[0278](S)-2-[3-(2-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 548;

[0279](S)-2-[3-(4-ethoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 558;

[0280](S)-2-[3-(4-methylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 528;

[0281](S)-2-[3-(2-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenyipropionamide,ESI 544;

[0282](S)-2-[3-(4-ethoxycarbonylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 586;

[0283](R)-2-[3-(3-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 548;

[0284](R)-2-[3-(4-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 582;

[0285](R)-2-[3-(2-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 548;

[0286](R)-2-[3-(4-ethoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 558;

[0287](R)-2-[3-(2-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4yl)-3-phenylpropionamide,ESI 544;

[0288](R)-2-[3-(4-ethoxycarbonylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 586;

[0289]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-5-BOC-aminovaleramide,

[0290](S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 514;

[0291](R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 514;

[0292](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-cyclopropylpropionamide;

[0293]2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylsulfanylbutyramide,ESI 532;

[0294](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-propionamide,ESI 472;

[0295]2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,ESI 458;

[0296]2-[3-(5-chloropyridin-2-yl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide;

[0297](R)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide;

[0298](R)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 562;

[0299]2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-hexanoamide,ESI 514;

[0300](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide,ESI 534;

[0301](S)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylpentanoamide,

[0302](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylpentanoamide,

[0303](S)-2-[3-(4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 544;

[0304](S)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,

[0305](S)-2-[3-(4-fluorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 640;

[0306](S)-2-[3-(4-fluorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 532;

[0307](S)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,

[0308](R)-2-[3-(4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 544;

[0309](R)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,

[0310](R)-2-[3-(4-fluorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 640;

[0311](R)-2-[3-(4-iodophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 532;

[0312](S)-2-[3-(3-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 582;

[0313](R)-2-[3-(3-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,ESI 582.

EXAMPLE 2a

[0314] Removal of the BOC protecting group from2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-5-BOC-aminovaleramidegives the compound2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-5-aminovaleramide,hydrochloride, ESI 481.

EXAMPLE 3

[0315] Analogous reaction of 4-(morpholin-4-yl)aniline with

[0316] (S)-2-(3-phenylureido)-3-phenylpropionic acid,

[0317] 2-(3-phenylureido)valeric acid,

[0318] (R)-2-(3-phenylureido)-3-phenylpropionic acid,

[0319] 2-(3-phenylureido)-3-(3-cyanophenyl)propionic acid,

[0320] 2-[3-(4-chlorophenyl)ureido]caproic acid,

[0321] 2-[3-(4-chlorophenyl)ureido]-4-(methylsulfanyl)butyric acid,

[0322] (R)-2-[3-(4-chlorophenyl)ureido]propionic acid,

[0323] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylvaleric acid,

[0324] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylvaleric acid,

[0325] gives the following compounds:

[0326](S)-2-(3-phenylureido)-N-[4-(morpholin-4-yl)phenyl]-3-phenylpropionamide,ESI 445

[0327] 2-(3-phenylureido)-N-[4-(morpholin-4-yl)phenyl]valeramide, ESI397;

[0328](R)-2-(3-phenylureido)-N-[4-(morpholin-4-yl)phenyl]-3-phenylpropionamide,ESI 445;

[0329]2-(3-phenylureido)-N-[4-(morpholin-4-yl)-phenyl]-3-(3-cyanophenyl)-propionamide,ESI 470;

[0330]2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]caproamide, ESI445;

[0331]2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]-4-methylsulfanylbutyramide,ESI 463;

[0332](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]-propionamide,ESI 403;

[0333](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]-4-methylvaleramide,ESI 445;

[0334](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]-4-methylvaleramide,ESI 445.

EXAMPLE 4

[0335] Reaction of 1-(pyridin-4-yl)piperidin-4-ylmethylamine with

[0336] (S)-2-(3-phenylureido)-3-phenylpropionic acid,

[0337] (R)-2-(3-phenylureido)-3-phenylpropionic acid,

[0338] 2-(3-phenylureido)valeric acid,

[0339] (S)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0340] 2-[3-(4-chlorophenyl)ureido]caproic acid,

[0341] 2-[3-(4-chlorophenyl)ureido]-4-(methylsulfanyl)butyric acid,

[0342] (R)-2-[3-(4-chlorophenyl)ureido]propionic acid,

[0343] 2-[3-(4-chlorophenyl)ureido]-3-(thiophen-2-yl)propionic acid,

[0344] 2-[3-(4-chlorophenyl)ureido]-3-(indol-3-yl)propionic acid,

[0345] 2-[3-(4-chlorophenyl)ureido]valeric acid,

[0346] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylvaleric acid,

[0347] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylvaleric acid,

[0348] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0349] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylbutyric acid,

[0350] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylbutyric acid,

[0351] (R)-2-[3-(3-chloro-pyridin-6-yl)ureido]-2-phenylacetic acid,

[0352] 2-[3-(4-chlorophenyl)ureido]-3,3,3-trifluoropropionic acid,

[0353] 2-[3-(4-chlorophenyl)ureido]-2-(pyridin-2-yl)acetic acid,

[0354] (R)-2-[3-(4-chlorophenyl)ureido]-2-(tert-butyl)acetic acid,

[0355] (S)-2-[3-(4-chlorophenyl)ureido]-2-(tert-butyl)acetic acid,

[0356] 2-[3-(4-chlorophenyl)ureido]-2-(2-fluorophenyl)acetic acid,

[0357] (R)-2-[3-(4-chlorophenyl)ureido]-2-(4-fluorophenyl)acetic acid,

[0358] (S)-2-[3-(4-chlorophenyl)ureido]-2-(4-fluorophenyl)acetic acid,

[0359] (R)-2-[3-(4-chlorophenyl)ureido]-2-(4-hydroxyphenyl)acetic acid,

[0360] (S)-2-[3-(4-chlorophenyl)ureido]-2-(4-hydroxyphenyl)acetic acid,

[0361] 2-[3-(4-chlorophenyl)ureido]acetic acid,

[0362] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0363] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0364] 2-[3-(4-chlorophenyl)ureido]-2-(2,1,3-benzothiadiazol-5-yl)aceticacid,

[0365] analogously to Example 2 gives the following compounds:

[0366](S)-2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-phenylpropionamide,ESI 458

[0367](R)-2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-phenylpropionamide,ESI 458;

[0368]2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]valeramide,ESI 410;

[0369](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,ESI 478;

[0370](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]caproamide,ESI 458;

[0371]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-4-methylsulfanylbutyramide,ESI 476;

[0372](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]propionamide,ESI 416;

[0373]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(thiophen-2-yl)propionamide,ESI 498;

[0374]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(indol-3-yl)propionamide,ESI 531;

[0375]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-valeramide,ESI 444; IC₅₀ (Xa)=5.8×10⁻⁷ M;

[0376](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylvaleramide,ESI 459;

[0377](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylvaleramide,ESI 459; IC₅₀ (Xa)=4.1×10⁻⁷ M;

[0378](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,ESI 478; IC₅₀ (Xa)=5.5×10⁻⁸ M;

[0379](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylbutyramide,ESI 444;

[0380](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylbutyramide,ESI 444;

[0381](R)-2-[3-(3-chloropyridin-6-yl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,

[0382]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3,3,3-trifluoropropionamide,

[0383]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(pyridin-2-yl)acetamide,ESI 479;

[0384](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(tert-butyl)acetamide,ESI 458;

[0385](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(tert-butyl)acetamide,

[0386]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(2-fluorophenyl)acetamide,ESI 496;

[0387](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-fluorophenyl)acetamide,ESI496;

[0388](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-fluorophenyl)acetamide,

[0389](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-hydroxyphenyl)acetamide,ESI 494;

[0390](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-hydroxyphenyl)acetamide,

[0391]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-acetamide,ESI 402;

[0392](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-3-phenylpropionamide,ESI 492;

[0393](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-3-phenylpropionamide,ESI 492;

[0394]2-[3-(3-chloropyridin-6-yl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(2,1,3-benzothiadiazol-5-yl)acetamide,ESI 536.

EXAMPLE 5

[0395] Reaction of C-biphenyl-2yl-methylamine with

[0396] (S)-2-(3-phenylureido)-3-phenylpropionic acid,

[0397] (R)-2-(3-phenylureido)-3-phenylpropionic acid,

[0398] 2-(3-phenylureido)valeric acid,

[0399] analogously to Example 2 gives the following compounds:

[0400](S)-2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)-3-phenyl-propionamide,ESI 450;

[0401](R)-2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)-3-phenyl-propionamide,ESI 450;

[0402] 2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)valeramide, ESI 402.

EXAMPLE 6

[0403] Reaction of 2′-methylsulfonylbiphenyl-4-yl-methylamineanalogously to Example 2 with

[0404] (S)-2-(3-phenylureido)-3-phenylpropionic acid,

[0405] (R)-2-(3-phenylureido)-3-phenylpropionic acid,

[0406] 2-(3-phenylureido)valeric acid,

[0407] gives the following compounds:

[0408](S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)-3-phenylpropionamide,ESI 528;

[0409](R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)-3-phenylpropionamide,ESI 528;

[0410]2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)valeramide,ESI 480.

EXAMPLE 7

[0411] Reaction of 1-(pyridin-4-yl)piperidin-4-ylamine analogously toExample 2 with

[0412] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0413] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0414] 2-[3-(4-chlorophenyl)ureido]pentanoic acid,

[0415] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0416] gives the following compounds:

[0417](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-3-phenylpropionamide;

[0418](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-2-phenylacetamide,hydrochloride, ESI 464;

[0419]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-pentanoamide,ESI 430;

[0420](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)-piperidin-4-yl]-3-phenylpropionamide,hydrochloride, ESI 478.

EXAMPLE 8

[0421] Reaction of 2′-tert-butylaminosulfonylbiphenyl-4-ylamineanalogously to Example 2 with

[0422] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0423] gives the following compound:

[0424](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-tert-butylaminosulfonylbiphenyl-4-yl)-3-phenylpropionamide,

[0425] and removal of the protecting group gives the compound

[0426](R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-aminosulfonylbiphenyl-4-yl)-3-phenylpropionamide.

EXAMPLE 9

[0427] Reaction of 1-(tetrahydropyran-4-yl)piperidin-4-ylamineanalogously to Example 2 with

[0428] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid

[0429] gives the following compound:

[0430](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-3-phenylpropionamide.

EXAMPLE 10

[0431] Reaction of 1-isopropylpiperidin-4-ylamine with

[0432] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0433] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0434] 2-[3-(4-chlorophenyl)ureido]valeric acid,

[0435] (S)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0436] analogously to Example 2 gives the following compounds:

[0437](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,hydrochloride;

[0438](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,hydrochloride, ESI 443;

[0439]2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]valeramide,hydrochloride, ESI 395;

[0440](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,hydrochloride, ESI 429.

EXAMPLE 11

[0441] Reaction of 1-(tetrahydropyran-4-yl)-piperidin-4-ylmethylaminewith

[0442] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0443] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0444] analogously to Example 2 gives the following compounds:

[0445](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-ylmethyl]-3-phenylpropionamide;

[0446](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-ylmethyl]-2-phenylacetamide,ESI 471.

EXAMPLE 12

[0447] Reaction of 4-(2-oxopiperidin-1-yl)aniline with

[0448] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0449] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0450] analogously to Example 2 gives the following compound:

[0451](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-phenylpropionamide,ESI 491,

[0452](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-phenylpropionamide,ESI 491.

EXAMPLE 13

[0453] Reaction of 4-(3-oxomorpholin-4-yl)phenylamine with

[0454] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid

[0455] analogously to Example 2 gives the following compound:

[0456](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-phenylpropionamide.

EXAMPLE 14

[0457] 14.1 2.0 g of chlorophenyl isocyanate and 100 mg of dibutyltindilaurate are added to a solution of 2.0 g of D/L-mandelic acid in 20 mlof dichloromethane, and the mixture is stirred at room temperature for18 hours. Conventional work-up gives2-[N-(4-chlorophenyl)carbamoyloxy]-2-phenylacetic acid (“CA”), ESI 306.

[0458] 14.2 36 ml of 4-methylmorpholine are added to a solution of 100mg of “CA”, 63 mg of 1-(pyridin-4-yl)piperidin-4-ylmethylamine, 63 mg ofDAPECI and 45 mg of HOBt in 2 ml of DMF, and the mixture is stirred atroom temperature for 18 hours. Conventional work-up gives2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-phenylacetamide,ESI 479,

[0459] IC₅₀ (Xa)=7.1×10⁻⁸ M.

[0460] The following compounds are obtained analogously starting from(R)- and (S)-mandelic acid:

[0461](S)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]-2-phenylacetamide,hydrochloride, ESI 479 and

[0462](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]-2-phenylacetamide,hydrochloride, ESI 479,

[0463] Analogous reaction of 1-(pyridin-4-yl)piperidin-4-ylmethylaminewith

[0464] 2-[N-(4-chlorophenyl)carbamoyloxy]acetic acid,

[0465] 2-[N-(4-chlorophenyl)carbamoyloxy]propionic acid,

[0466] 2-[N-(4-chlorophenyl)carbamoyloxy]-2-(2-fluorophenyl)acetic acid,

[0467] 2-[N-(4-chlorophenyl)carbamoyloxy]-2-(4-chlorophenyl)acetic acid,

[0468] 2-[N-(4-chlorophenyl)carbamoyloxy]-2-(2-chlorophenyl)acetic acid,

[0469] (R)-2-[N-(4-chlorophenyl)carbamoyloxy]-2-(3-chlorophenyl)aceticacid,

[0470] gives the following compounds:

[0471]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]acetamide,ESI 403;

[0472]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]propionamide,ESI 417.

[0473]2-[N-(4-chlorophenyl)carbamoyloxy]-2-(2-fluorophenyl)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]acetamide,ESI 497;

[0474]2-[N-(4-chlorophenyl)carbamoyloxy]-2-(4-chlorophenyl)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]acetamide,ESI 513;

[0475]2-[N-(4-chlorophenyl)carbamoyloxy]-2-(2-chlorophenyl)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]acetamide,ESI 513;

[0476](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-2-(3-chlorophenyl)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]acetamide,ESI 513;

EXAMPLE 15

[0477] Reaction of 1-cyclopentylpiperidin-4-ylamine with

[0478] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0479] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0480] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0481] analogously to Example 2 gives the following compounds:

[0482](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-3-phenylpropionamide,ESI 469;

[0483](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-3-phenylpropionamide,ESI 469;

[0484](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-2-phenylacetamide,ESI 455.

EXAMPLE 16

[0485] Reaction of 4-(2-oxopyrrolidin-1-yl)aniline with

[0486] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0487] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0488] analogously to Example 2 gives the following compounds:

[0489](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-phenylpropionamide,ESI 477,

[0490](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-phenylpropionamide.

EXAMPLE 17

[0491] Reaction of 4-(piperidin-1-yl)aniline with

[0492] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0493] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0494] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0495] analogously to Example 2 gives the following compounds:

[0496](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)-phenyl]-3-phenylpropionamide,ESI 477,

[0497](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)-phenyl]-3-phenylpropionamide,ESI 477;

[0498](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)-phenyl]-2-phenylacetamide,ESI 463.

EXAMPLE 18

[0499] Reaction of 4-diethylaminoaniline with

[0500] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0501] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0502] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0503] analogously to Example 2 gives the following compounds:

[0504](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-3-phenylpropionamide,ESI 465;

[0505](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-3-phenylpropionamide,ESI 465;

[0506](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-2-phenylacetamide,ESI 451.

[0507] The compounds

[0508](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-dimethylaminophenyl]-3-phenylpropionamide,ESI 437;

[0509](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-dimethylaminophenyl]-3-phenylpropionamide,ESI 437,

[0510] are obtained analogously.

EXAMPLE 19

[0511] Reaction of 1-(tetrahydropyran-4-yl)piperidin-4-ylamine with

[0512] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid

[0513] analogously to Example 2 gives the following compound:

[0514](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-3-phenylpropionamide,ESI 485.

EXAMPLE 20

[0515] Reaction of 4-aminomethyl-1-BOC-piperidine with

[0516] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0517] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0518] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid,

[0519] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid,

[0520] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0521] analogously to Example 2 gives the following compounds:

[0522](S)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3-phenylpropionamide,

[0523](R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3-phenylpropionamide,

[0524](S)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4-methylpentanoamide,

[0525](R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4-methylpentanoamide,

[0526](R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-2-phenylacetamide,ESI 501.

EXAMPLE 20a

[0527] Removal of the BOC protecting group from the compounds obtainedin Example 20 using HCl in dioxane gives the following piperidinederivatives

[0528](S)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-3-phenylpropionamide,hydrochloride, ESI 415;

[0529](R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-3-phenylpropionamide,hydrochloride, ESI 415;

[0530](S)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-4-methylpentanoamide,hydrochloride, ESI 381;

[0531](R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-4-methylpentanoamide,hydrochloride, ESI 381;

[0532](R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-2-phenylacetamide,hydrochloride, ESI 401.

EXAMPLE 21

[0533] Reaction of (1-isopropylpiperidin-4-yl)methylamine with

[0534] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0535] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0536] (S)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid,

[0537] (R)-2-[3-(4-chlorophenyl)ureido]-4-methylpentanoic acid,

[0538] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0539] analogously to Example 2 gives the following compounds:

[0540](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,ESI 457;

[0541](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,ESI 457;

[0542](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-4-methylpentanoamide,ESI 423;

[0543](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-4-methylpentanoamide,ESI 423;

[0544](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,ESI 443.

EXAMPLE 21a

[0545] Partitioning of(R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-2-phenylacetamide,hydrochloride, between ethyl acetate and 1 N NaOH, followed by removalof the solvent, gives the free base.

[0546] 120 mg of(R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-2-phenylacetamideis dissolved in 4 ml of dichloromethane and 2 ml of acetone, and 0.1 mlof acetic acid and 300 mg of sodium triacetoxyboro-hydride are added,and the mixture is stirred at room temperature for 18 hours. Saturatedaqueous ammonium chloride solution is then added, and the organic phaseis separated off. Removal of the solvent gives(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,ESI 443.

EXAMPLE 22

[0547] Reaction of 4-(4-BOC-piperazin-1-yl)aniline with

[0548] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0549] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0550] analogously to Example 2 gives the following compounds:

[0551](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-phenylpropionamide,hydrochloride,

[0552](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(4-BOC-piperazin-1-yl)-phenyl]-3-phenylpropionamide,hydrochloride,

[0553] and removal of BOC groups therefrom gives

[0554](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperazin-1-yl)-phenyl]-3-phenylpropionamide,hydrochloride, ESI 478,

[0555](S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperazin-1-yl)-phenyl]-3-phenylpropionamide,hydrochloride, ESI 478,

EXAMPLE 23

[0556] Reaction of 1-cyclohexylpiperidin-4-ylamine with

[0557] (S)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0558] (R)-2-[3-(4-chlorophenyl)ureido]-3-phenylpropionic acid,

[0559] (R)-2-[3-(4-chlorophenyl)ureido]-2-phenylacetic acid,

[0560] analogously to Example 2 gives the following compounds:

[0561](S)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-3-phenylpropionamide,hydrochloride, ESI 483;

[0562](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-3-phenylpropionamide,hydrochloride, ESI 483;

[0563](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-2-phenylacetamide.

EXAMPLE 24

[0564] Reaction of 4-(morpholin-4-yl)aniline with

[0565] 2-[N-(4-chlorophenyl)carbamoyloxy]acetic acid,

[0566] 2-[N-(4-chlorophenyl)carbamoyloxy]propionic acid,

[0567] 2-[N-(4-chlorophenyl)carbamoyloxy]-2-phenylacetic acid,

[0568] analogously to Example 14 gives the following compounds:

[0569]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]acetamide,ESI 390;

[0570]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]propionamide,ESI 404;

[0571]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]-2-phenylacetamide,ESI 466.

EXAMPLE 25

[0572] Reaction of “BB” with

[0573] 2-[N-(4-chlorophenyl)carbamoyloxy]acetic acid,

[0574] 2-[N-(4-chlorophenyl)carbamoyloxy]propionic acid,

[0575] 2-[N-(4-chlorophenyl)carbamoyloxy]-2-phenylacetic acid,

[0576] analogously to Example 14 gives the following compounds:

[0577]2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,ESI 459;

[0578]2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)propionamide,ESI 473;

[0579]2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide.

EXAMPLE 26

[0580] The following are obtained analogously to Example 14:

[0581](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(piperidin-4-ylmethyl)-2-phenylacetamide,trifluoroacetate, ESI 402;

[0582](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-isopropylpiperidin-4-yl-methyl)-2-phenylacetamide,hydrochloride, ESI 444;

[0583](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(4-dimethylaminobenzyl)-2-phenylacetamide,ESI 438;

[0584](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-benzyl]-2-phenylacetamide,ESI 480;

[0585](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-cyclohexylpiperidin-4-ylmethyl)-2-phenylacetamide,hydrochloride, ESI 485;

[0586](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-ylmethyl]-2-phenylacetamide,hydrochloride, ESI 485;

[0587](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-cyclopentylpiperidin-4-ylmethyl)-2-phenylacetamide,hydrochloride, ESI 470;

[0588](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(2-methylpropyl)-piperidin-4-ylmethyl]-2-phenylacetamide,hydrochloride, ESI 458;

[0589](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(1-ethylpropyl)-piperidin-4-ylmethyl]-2-phenylacetamide,hydrochloride, ESI 472;

[0590](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxo-2H-pyridin-1-yl)-benzyl]-2-phenylacetamide,ESI 488;

[0591](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxoazepan-1-yl)-phenyl]-2-phenylacetamide,ESI 492;

[0592]2-[N-(4-cyanophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-2-phenylacetamide,ESI 470;

[0593]2-[N-(3-cyanophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-2-phenylacetamide,ESI 470;

[0594](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,ESI 478;

[0595]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-2-cyclohexylacetamide,ESI 485;

[0596](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]-2-phenylacetamide,ESI 466;

[0597]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)-piperidin-4-yl-methyl]-3,3,3-trifluoropropionamide,ESI 471;

[0598](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(piperazin-4-yl)-phenyl]-2-phenylacetamide,ESI 465;

[0599](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[3-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,ESI 478;

[0600](R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxopiperazin-1-yl)-phenyl]-2-phenylacetamide,ESI 479;

[0601]2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(2-thienyl)acetamide,ESI 485.

EXAMPLE 27

[0602] The following are obtained analogously to Example 4:

[0603]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-phenylacetamide,ESI 478;

[0604]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-4,4,4-trifluorobutyramide,ESI 484;

[0605]2-(3-phenylureido)-N-[4-(2-oxopiperidin-1-yl)-phenyl]-3-(4-cyanophenyl)propionamide,ESI 482;

[0606]2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-cyanophenyl)propionamide,ESI 483;

[0607]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-cyanophenyl)propionamide,ESI 517;

[0608]2-(3-phenylureido)-N-[4-(2-oxopiperidin-1-yl)-phenyl]-3-(3-aminocarbonylphenyl)propionamide,ESI 500;

[0609]2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-aminocarbonylphenyl)propionamide,ESI 501;

[0610]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-aminocarbonylphenyl)propionamide,ESI 535;

[0611](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,ESI 477;

[0612](R)-2-[3-(4-chlorophenyl)ureido]-N-[3-methyl-4-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,ESI 491;

[0613](R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperazin-1-yl)-phenyl]-2-phenylacetamide,ESI 478;

[0614]2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(2-thienyl)acetamide,ESI 484;

[0615]2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperazin-1-yl)-phenyl]-2-(2-thienyl)acetamide,ESI 484;

[0616]2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-2-(2-thienyl)acetamide,ESI 480;

[0617](R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-ylmethyl]-2-(2-thienyl)acetamide,ESI 449.

[0618] The following examples relate to medicaments:

EXAMPLE A

[0619] Injection Vials

[0620] A solution of 100 g of an active ingredient of the formula I and5 g of disodium hydrogenphosphate in 3 l of bidistilled water isadjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered,transferred into injection vials, lyophilised under sterile conditionsand sealed under sterile conditions. Each injection vial contains 5 mgof active ingredient.

EXAMPLE B

[0621] Suppositories

[0622] A mixture of 20 g of an active ingredient of the formula I with100 g of soya lecithin and 1400 g of cocoa butter is melted, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C

[0623] Solution

[0624] A solution is prepared from 1 g of an active ingredient of theformula I, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 gof benzalkonium chloride in 940 ml of bidistilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D

[0625] Ointment

[0626] 500 mg of an active ingredient of the formula I are mixed with99.5 g of Vaseline under aseptic conditions.

EXAMPLE E

[0627] Tablets

[0628] A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F

[0629] Coated Tablets

[0630] Tablets are pressed analogously to Example E and subsequentlycoated in a conventional manner with a coating of sucrose, potatostarch, talc, tragacanth and dye.

EXAMPLE G

[0631] Capsules

[0632] 2 kg of active ingredient of the formula I are introduced intohard gelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H

[0633] Ampoules

[0634] A solution of 1 kg of active ingredient of the formula I in 60 lof bidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Compounds of the formula I

in which D is phenyl or pyridyl, each of which is unsubstituted ormonosubstituted or polysubstituted by Hal, A, OR², N(R²)₂, NO₂, CN,COOR² or CON(R²)₂, R¹ is H, Ar, Het, cycloalkyl or A, which may besubstituted by OR², SR², N(R²)₂, Ar, Het, cycloalkyl, CN, COOR² orCON(R²)₂, R² is H or A, E is phenylene, which may be monosubstituted orpolysubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR² or CON(R²)₂, oris piperidine-1,4-diyl, W is Ar, Het or N(R²)₂ and, ifE=piperidine-1,4-diyl, is alternatively R² or cycloalkyl, X is NH or O,A is unbranched or branched alkyl having 1-10 carbon atoms, in which oneor two CH₂ groups may be replaced by O or S atoms and/or by —CH═CH—groups and/or in addition 1-7 H atoms may be replaced by F, Ar is phenylwhich is unsubstituted or monosubstituted, disubstituted ortrisubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂, NR²COA,NR²SO₂A, COR², SO₂NR², SO₃H or S(O)_(m)A, Het is a monocyclic orbicyclic, saturated, unsaturated or aromatic heterocyclic radical havingfrom 1 to 4 N, O and/or S atoms, which may be unsubstituted ormonosubstituted, disubstituted or trisubstituted by Hal, A, OR², N(R²)₂,NO₂, CN, COOR², CON(R²)₂, NR²COA, NR²SO₂A, COR², SO₂NR², SO₃H, S(O)_(m)Aand/or carbonyl oxygen, Hal is F, Cl, Br or I, n is 0 or 1, m is 0, 1 or2, and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.
 2. Compoundsaccording to claim 1 in which D is phenyl which is unsubstituted ormonosubstituted or disubstituted by Hal, A, OR² or COOR², or pyridylwhich is unsubstituted or monosubstituted by Hal, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 3. Compounds according toclaim 1 in which Het is a monocyclic or bicyclic, saturated, unsaturatedor aromatic heterocyclic radical having from 1 to 2 N, O and/or S atoms,which may be unsubstituted or monosubstituted by carbonyl oxygen, andtheir pharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 4. Compounds according toclaim 1 in which Ar is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR², SO₂A, SO₂NH₂, COOR² orCN, and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.
 5. Compoundsaccording to claim 1 in which D is phenyl which is unsubstituted ormonosubstituted or disubstituted by Hal, A, hydroxyl, methoxy, ethoxy,hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, or pyridyl which isunsubstituted or monosubstituted by Hal, and their pharmaceuticallyusable derivatives, solvates and stereoisomers, including mixturesthereof in all ratios.
 6. Compounds according to claim 1 in which R¹ isH, phenyl or alkyl having 1-6 carbon atoms, which may be substituted bythiophene, imidazole, indole, SR², cycloalkyl or phenyl, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 7. Compounds according toclaim 1 in which E is 1,4-phenylene or 1,4-piperidinyl, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 8. Compounds according toclaim 1 in which Ar is phenyl which is unsubstituted or monosubstituted,disubstituted or trisubstituted by Hal, A, OR², SO₂A, SO₂NH₂, COOR² orCN, Het is a monocyclic or bicyclic, saturated, unsaturated or aromaticheterocyclic radical having from 1 to 2 N, O and/or S atoms, which maybe unsubstituted or monosubstituted by carbonyl oxygen, W is Ar, Het orN(R²)₂ and, if E=piperidine-1,4-diyl, is alternatively R², and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 9. Compounds according toclaim 1 in which Ar is phenyl which is unsubstituted or monosubstitutedby Hal, A, OA, SO₂A, COOR², SO₂NH₂ or CN, Het is thienyl, imidazolyl,pyridyl, indolyl, piperidinyl, piperazinyl, pyrazinyl,2-oxo-2H-pyrazin-1-yl, 2-oxopiperazinyl, morpholinyl,tetrahydropyran-4-yl, 3-oxo-morpholin-4-yl, 2-oxopyrrolidin-1-yl or2-oxopiperidin-1-yl, W is Ar, Het or N(R²)₂ and, ifE=piperidine-1,4-diyl, is alternatively R², and their pharmaceuticallyusable derivatives, solvates and stereoisomers, including mixturesthereof in all ratios.
 10. Compounds according to claim 1 in which D isphenyl which is unsubstituted or monosubstituted or disubstituted byHal, A, OR² or COOR², or pyridyl which is unsubstituted ormonosubstituted by Hal, R¹ is H, phenyl or alkyl having 1-6 carbonatoms, which may be substituted by thiophene, imidazole, indole, SR²,cycloalkyl or phenyl, R² is H or A, E is 1,4-phenylene or1,4-piperidinyl, W is Ar, Het or N(R²)₂ and, if E=piperidine-1,4-diyl,is alternatively R², A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atomsor CF₃, Ar is phenyl which is unsubstituted or monosubstituted ordisubstituted by Hal, A, OA, SO₂A, COOR², SO₂NH₂ or CN, Het is thienyl,imidazolyl, pyridyl, indolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, pyrazinyl, 2-oxo-2H-pyrazin-1-yl, morpholinyl,tetrahydropyran-4-yl, 3-oxomorpholin-4-yl, 2-oxopyrrolidin-1-yl or2-oxopiperidin-1-yl, Hal is F, Cl or Br, n is 0 or 1, m is 1 or 2, andtheir pharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 11. Compounds according toclaim 1 in which D unsubstituted or monosubstituted by Hal, or pyridylwhich is unsubstituted or monosubstituted by Hal, R¹ is H, phenyl oralkyl having 1-6 carbon atoms, which may be substituted by thiophene,imidazole, indole, SR², cycloalkyl or phenyl, R² is H or A, E is1,4-phenylene, W is 2-methylsulfonylphenyl, X is NH or O, A is alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃, n is 0, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 12. Compounds according toclaim 1 in which D is phenyl which is unsubstituted or monosubstitutedby Hal, or pyridyl which is unsubstituted or monosubstituted by Hal, R¹is H, phenyl or alkyl having 1-6 carbon atoms, which may be substitutedby thiophene, imidazole, indole, SR², cycloalkyl or phenyl, R² is H orA, E is 1,4-piperidinyl, W is Het, Het is thienyl, imidazolyl, pyridyl,indolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, pyrazinyl,2-oxo-2H-pyrazin-1-yl, morpholinyl, tetrahydropyran-4-yl,3-oxomorpholin-4-yl or 2-oxopiperidin-1-yl, X is NH or O, A is alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃, n is 0 or 1, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 13. Compounds according toclaim 1 in which R¹ is H, phenyl or alkyl having 1-6 carbon atoms, whichmay be substituted by thiophene, imidazole, indole, SR², cycloalkyl orphenyl, or phenyl or pyridyl, each of which is monosubstituted by Hal orOH, and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.
 14. Compoundsaccording to claim 1 in which D is phenyl which is unsubstituted ormonosubstituted by Hal, or pyridyl which is unsubstituted ormonosubstituted by Hal, R¹ is H, phenyl or alkyl having 1-6 carbonatoms, which may be substituted by thiophene, imidazole, indole, SR²,cycloalkyl or phenyl, R² is H or A, E is 1,4-piperidinyl, W is Het, R²or cycloalkyl, Het is thienyl, imidazolyl, pyridyl, indolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, pyrazinyl,2-oxo-2H-pyrazin-1-yl, morpholinyl, tetrahydropyran-4-yl,3-oxomorpholin-4-yl or 2-oxopiperidin-1-yl, X is NH or O, A is alkylhaving 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃, n is 0 or 1, and theirpharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios.
 15. Compounds according toclaim 1(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)propionamide,(S)-2-(3-pyridin-2-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(thiophen-2-yl)propionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(3H-imidazol-4-yl)propionamide,(R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)hexanoamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylsulfanylbutyramide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-methylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-(3-pyridin-4-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(S)-2-(3-pyridin-4-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(R)-2-(3-pyridin-2-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(R)-2-(3-pyridin-3-ylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)pentanoamide,(S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(pyridin-3-yl)propionamide,(S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-(indol-3-yl)propionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)propionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,(S)-2-[3-(3-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(2-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-ethoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-methylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(2-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-ethoxycarbonylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(3-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(2-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-ethoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(2-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-ethoxycarbonylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-5-BOC-aminovaleramide,(S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-cyclopropylpropionamide,2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylsulfanylbutyramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-propionamide,2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,2-[3-(5-chloro-pyridin-2-yl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)hexanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-4-methylpentanoamide,(S)-2-[3-(4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-iodophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(4-fluorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(3-fluoro-4-methoxyphenyl)ureido]-N-(2′methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-methoxyphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-bromophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-iodophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-fluorophenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(S)-2-[3-(3-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(3-trifluoromethylphenyl)ureido]-N-(2′-methylsulfonylbiphenyl-4-yl)-3-phenylpropionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-yl)-5-aminovaleramide,(S)-2-(3-phenylureido)-N-[4-(morpholin-4-yl)-phenyl]-3-phenylpropionamide,2-(3-phenylureido)-N-[4-(morpholin-4-yl)-phenyl]valeramide,(R)-2-(3-phenylureido)-N-[4-(morpholin-4-yl)-phenyl]-3-phenylpropionamide,2-(3-phenylureido)-N-[4-(morpholin-4-yl)-phenyl]-3-(3-cyanophenyl)propionamide,2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)-phenyl]caproamide,2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)-phenyl]4-methylsulfanylbutyramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)-phenyl]-propionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)-phenyl]-4-methylvaleramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(morpholin-4-yl)phenyl]-4-methylvaleramide,(S)-2-(3-phenylureido)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]-3-phenylpropionamide,(R)-2-(3-phenylureido)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]-3-phenylpropionamide,2-(3-phenylureido)-N-[1-(pyridin-4-yl)-piperidin-4-ylmethyl]valeramide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]caproamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-4-methylsulfanylbutyramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]propionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(thiophen-2-yl)propionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(indol-3-yl)propionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]valeramide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylvaleramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylvaleramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylbutyramide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-4-methylbutyramide,(R)-2-[3-(3-chloropyridin-6-yl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-phenylacetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3,3,3-trifluoropropionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(pyridin-2-yl)acetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(tert-butyl)acetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(tert-butyl)acetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(2-fluorophenyl)acetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-fluorophenyl)acetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-fluorophenyl)acetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-hydroxyphenyl)acetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(4-hydroxyphenyl)acetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-acetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-3-phenylpropionamide,2-[3-(3-chloropyridin-6-yl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(2,1,3-benzothiadiazol-5-yl)acetamide,(S)-2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)-3-phenylpropionamide,(R)-2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)-3-phenylpropionamide,2-(3-phenylureido)-N-(biphenyl-2-ylmethyl)valeramide,(S)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)-3-phenylpropionamide,(R)-2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)-3-phenylpropionamide,2-(3-phenylureido)-N-(2′-methylsulfonylbiphenyl-4-ylmethyl)valeramide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl]-3-phenylpropionamid;(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl]-2-phenylacetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl]pentanoamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-tert-butyl-aminosulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(2′-aminosulfonylbiphenyl-4-yl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]valeramide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)piperidin-4-ylmethyl]-3phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)piperidin-4-ylmethyl]-2phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(3-oxo-morpholin-4-yl)phenyl]-3-phenylpropionamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2phenylacetamide,(S)-2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2phenylacetamide,(R)-2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2phenylacetamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]acetamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]propionamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-2-(2-fluorophenyl)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]acetamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-2-(4-chlorophenyl)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]acetamide,2-[N-(4-chlorophenyl)-carbamoyloxy]-2-(2-chlorophenyl)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]acetamide,(R)-2-[N-(4-chlorophenyl)-carbamoyloxy]-2-(3-chlorophenyl)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]acetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclopentylpiperidin-4-yl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)phenyl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperidin-1-yl)phenyl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-3phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-3phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-diethylaminophenyl]-2phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-dimethylaminophenyl]-3phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-dimethylaminophenyl]-3phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]-3phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(1-BOC-piperidin-4-ylmethyl)-2-phenylacetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-(piperidin-4-ylmethyl)-2-phenylacetamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-4-methylpentanoamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-yl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(4-bOC-piperazin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(4-bOC-piperazin-1-yl)phenyl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperazin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[4-(piperazin-1-yl)phenyl]-3-phenylpropionamide,(S)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-3-phenylpropionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-cyclohexylpiperidin-4-yl]-2-phenylacetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]acetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]propionamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]-2-phenylacetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)propionamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-(2′-methylsulfonylbiphenyl-4-yl)-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(piperidin-4-yl-methyl)-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-isopropylpiperidin-4-yl-methyl)-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(4-dimethylamino-benzyl)-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-benzyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-cyclohexylpiperidin-4-yl-methyl)-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(tetrahydropyran-4-yl)-piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-(1-cyclopentylpiperidin-4-yl-methyl)-2-phenyl-acetamid(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(2-methyl-propyl)-piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(1-ethyl-propyl)-piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxo-2H-pyridin-1-yl)-benzyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxo-azepan-1-yl)-phenyl]-2-phenylacetamide,2-[N-(4-cyanophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,2-[N-(3-cyanophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-cyclohexylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(morpholin-4-yl)-phenyl]-2-phenylacetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-3,3,3-trifluoropropionamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(piperazin-4-yl)-phenyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[3-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,(R)-2-[N-(4-chlorophenyl)carbamoyloxy]-N-[4-(2-oxopiperazin-1-yl)-phenyl]-2-phenylacetamide,2-[N-(4-chlorophenyl)carbamoyloxy]-N-[1-(pyridin-4-yl)piperidin-4-yl-methyl]-2-(2-thienyl)acetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-phenylacetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-4,4,4-trifluorobutyramide,2-(3-phenylureido)-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-(4-cyanophenyl)propionamide,2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-cyanophenyl)propionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-cyanophenyl)propionamide,2-(3-phenylureido)-N-[4-(2-oxopiperidin-1-yl)phenyl]-3-(3-aminocarbonylphenyl)propionamide,2-(3-phenylureido)-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-aminocarbonyl-phenyl)propionamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-3-(3-aminocarbonyl-phenyl)propionamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperidin-1-yl)phenyl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[3-methyl-4-(2-oxopiperidin-1-yl)-phenyl]-2-phenylacetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperazin-1-yl)phenyl]-2-phenylacetamide,2-[3-(4-chlorophenyl)ureido]-N-[1-(pyridin-4-yl)piperidin-4-ylmethyl]-2-(2-thienyl)acetamide,2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxopiperazin-1-yl)phenyl]-2-(2-thienyl)acetamide,2-[3-(4-chlorophenyl)ureido]-N-[4-(2-oxo-2H-pyrazin-1-yl)phenyl]-2-(2-thienyl)acetamide,(R)-2-[3-(4-chlorophenyl)ureido]-N-[1-isopropylpiperidin-4-ylmethyl]-2-(2-thienyl)acetamide,and their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios.
 16. Process forthe preparation of compounds of the formula I according to claims 1-15and their pharmaceutically usable derivatives, solvates andstereoisomers, characterised in that a) a compound of the formula II

in which R¹, E, W, X and n are as defined in claim 1, is reacted with acompound of the formula III D—N═C═O  III in which D is as defined inclaim 1, or b) a compound of the formula IV H₂N—(CH₂)_(n)—E—W  IV,inwhich E, W and n are as defined in claim 1, is reacted with a compoundof the formula V

in which L is Cl, Br, I or a free or reactively functionally modified OHgroup, and R¹, X and D are as defined in claim 1, or d) compounds of theformula I are liberated from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent, or c) a base oracid of the formula I is converted into one of its salts.
 17. Compoundsof the formula I according to one or more of claims 1 to 15 asinhibitors of coagulation factor Xa.
 18. Compounds of the formula Iaccording to one or more of claims 1 to 15 as inhibitors of coagulationfactor VIIa.
 19. Medicament comprising at least one compound of theformula I according to one or more of claims 1 to 15 and/or itspharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios, and optionally excipientsand/or assistants.
 20. Medicament comprising at least one compound ofthe formula I according to one or more of claims 1 to 15 and/or itspharmaceutically usable derivatives, solvates and stereoisomers,including mixtures thereof in all ratios, and at least one furthermedicament active ingredient.
 21. Use of compounds according to one ormore of claims 1 to 15 and/or their physiologically acceptable salts andsolvates for the preparation of a medicament for the treatment ofthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, tumours, tumour diseases and/or tumour metastases.
 22. Set(kit) consisting of separate packs of (a) an effective amount of acompound of the formula I according to one or, more of claims 1 to 15and/or its pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, and (b) aneffective amount of a further medicament active ingredient.
 23. Use ofcompounds of the formula I according to one or more of claims 1 to 15and/or their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of thrombosis, myocardialinfarction, arteriosclerosis, inflammation, apoplexia, angina pectoris,restenosis after angioplasty, claudicatio intermittens, tumours, tumourdiseases and/or tumour metastases, in combination with at least onefurther medicament active ingredient.